1. Field of the invention
The present invention relates to novel .alpha.,.alpha.-trehalose derivatives having anti-tumor activity.
2. Background information
Derivatives of .alpha.,.alpha.-trehalose, such as 6,6'-dimycolate of .alpha.,.alpha.-trehalose extracted from cell wall of a tubercle bacillus, have attracted considerable attention, as they have various immuno-pharmacological activities such as immunoadjuvant activity, ability of granuloma formation, ability of macrophage activation, ability of enhancing non-specific protection, anti-tumor activity, etc. [Yakugaku Zasshi, 107, 37-45 (1987) and Kekkaku, 63 (3), 41-54 (1988)]. Particular chemical structures of these liposaccharides, however, have not been well established due to the fact that their mycolic acid moieties, forming the most notable characteristic of cell walls of acid-fast bacteria, are long-chain fatty acid (having 60 to 88 carbon atoms) of extremely strong hydrophobic property and that they are unstable at elevated temperatures. In addition, these compounds are not appropriate for medical application because composition (such as number of carbon atoms, unsaturation and substitution) of their mycolic acid moieties varies from one bacterial species to another and thus products with uniform composition cannot be obtained. Furthermore, particularly the liposaccharides having mycolic acid moieties of 70 to 80 carbon atoms have fault that they are highly toxic.
Among other .alpha.,.alpha.-trehalose derivatives, there may be mentioned 2,3,6'-trimycolate of .alpha.,.alpha.-trehalose, obtained from Rhodococcus aurantiacus, which has very unusual unsymmetrical structure [FEBS letters, 203, 239-242 (1986)] and 2,6'-dimycolate of .alpha.,.alpha.-trehalose extracted from the same bacterium [60th Annual Meeting of Biochemical Society of Japan, Oct. 1987]. However, pharmacological activities of these unsymmetrical mycolic ester of .alpha.,.alpha.-trehalose have not been sufficiently clarified and neither structure nor composition of their mycolic acid moieties have been determined.
Other difatty-acid esters of .alpha.,.alpha.-trehalose have been described [U.S. Pat. No. 4,612,304; CA-A-1,202,622; JP-B-50478/1987; JP-A-46294/1984; JP-A-157097/1984; JP-A-289038/1986; JP-A-53926/1987; JP-A-174094/1987 and Chem. Pharm. Bull. 33, 4455 (1985)]. All these compounds are substituted with fatty acid residues at symmetrical (e.g. 6,6')positions of .alpha.,.alpha.-trehalose.
Also, there have been known 2-palmitoyl, 2,2'-dipalmitoyl and 2,3,2'-tripalmitoyl derivatives of .alpha.,.alpha.-trehalose by J. Chem. Soc. Perkin I, 1980, 1940-1943, 6-(3-hydroxy-2-tetradecanyloctadecanoyl)ester by Carbohydrate Res., 125, 323-328 (1984), 6,6'-bis-(3-hydroxy-2-tetracosanylhydroxyhexacontanoyl)ester by Chem. Phys. Lipids, 16, 91-106 (1976), 2,6,6'-tris(3-acetoxy-2-tetracosanyl-methoxyhexacontanoyl)ester by Bull. Soc. Chim. France, 1478-1482 (1956), 2,3,4,2'-esters by DE-A1-3248167, 2,3,6,2'-esters by Chem. Phys. Lipids, 29 241-266 (1981), 4,6,4',6'-tetrastearoyl ester by Chem. Pharm. Bull. 30, 1169-1174 (1982) and 4,6,4', 6',-esters by JP-A-157097/1984.
After an extensive study on the synthesis of glycolipids having long chain aliphatic acyl group as their lipid moieties, the present inventors have successfully prepared .alpha.,.alpha.-trehalose derivatives having mycolic acid or aliphatic acid moieties of defined chemical structure, uniform constitution and thus improved safety, particularly unsymmetrical derivatives (i.e. compounds except those having only the same acyl groups located at paired positions designated by numbers corresponding with each other).